Delivery of igf-1 in myocardial infarction

Abstract

Described herein are methods that result in less cell death resulting from myocardial infarction than would otherwise occur in an individual who has suffered myocardial infarction. Also described are compositions useful in reducing cell death post myocardial infarction.

What is claimed is: 
     
         1 . A stent bearing aluminum oxide (Al 2 O 3 ) and IGF-1, wherein the IGF-1 is adsorbed to the aluminum oxide. 
     
     
         2 . The stent of  claim 1 , wherein the aluminum oxide is a coating from about 0.5 nm to about 10 nm in thickness. 
     
     
         3 . The stent of  claim 2 , wherein the aluminum oxide coating is produced or placed on the stent by atomic layer deposition (ALD). 
     
     
         4 . A stent bearing a coating of aluminum oxide (Al 2 O 3 ) of thickness from about 0.5 nm to about 10 nm. 
     
     
         5 . The stent of  claim 4 , further comprising IGF-1 adsorbed to the aluminum oxide (Al 2 O 3 ). 
     
     
         6 . A stent coated with or bearing a slow-release composition comprising IGF-1 and at least one biocompatible slow release component. 
     
     
         7 . The stent of  claim 6 , wherein the composition comprises at least one component selected from the group consisting of: 50CP30L40-LL40 (PCL-02), Polyglycolide (PGA), Copolymers of glycolide, Glycolide/L-lactide copolymers (PGA/PLLA), Glycolide/trimethylene carbonate copolymers (PGS/TMC), Polylactides (PLA), Stereo-copolymers of PLA, Poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers, Copolyers of PLA, Lactide/tetramethylglycolide copolymers, Lactide/trimethylene carbonate copolymers, Lactide/α-valerolactone copolymers, Lactide/ε-caprolactone copolymers, Hyaluronic acid and its derivatives, Polydepsipeptides, PLA/polyethylene oxide copolymers, Unsymmetrical 3,6-substitute poly-1,4-dioxane-2,5-di-ones, Poly-βhydroxybutyrate (PHBA), PHBA A/β-hydroxyvalerate copolymers (PHBA/HVA), Poly-p-dioxanone (PDS), Poly-α-valerolactone, Poly-ε-caprolactone, Methylmethacrylate-N-vinyl pyrrolidine copolymers, Polyesteramides, Polyesters of oxalic acid, Polydihydropyranes, Polyalkyl-2-cyanoacrylates, Polyurethanes (PU), Polyvinylalcohol (PVA), Polypeptides, Poly-β-malic acid (PMLA), Poly-β-alcanoic acids and alginates. 
     
     
         8 . The stent of  claim 6  or  7 , wherein the slow release composition releases from about 1.0 ng of IGF-1 to about 100 ng of IGF-1 within 24 hours after introduction of the stent into an individual. 
     
     
         9 . The stent of any one of  claims 6 - 8 , wherein the IGF-1 content of the slow release composition is from about 1.0 ng IGF-1 to about 100 ng IGF-1. 
     
     
         10 . The stent of any one of  claims 6 - 9 , wherein the slow release composition releases from about 1.0 ng IGF-1 to about 100 ng IGF-1 into cardiac muscle within 48 hours after introduction into an individual. 
     
     
         11 . The stent of any one of  claims 6 - 10 , wherein the slow release composition releases from about 1.0 ng-2.0 ng, from about 1.0 ng-5.0 ng, from about 1.0 ng-10 ng, from about 1.0 ng-20 ng, from about 1.0 ng-30 ng, from about 1.0 ng-40 ng, from about 1.0 ng-60 ng, from about 1.0 ng-80 ng or from about 1.0 ng-100 ng IGF-1 within 48 hours after introduction into an individual. 
     
     
         12 . The stent of any one of  claims 6 - 11 , wherein the slow release composition releases from 1.0 ng-15 ng IGF-1 within 2 hours after introduction into an individual. 
     
     
         13 . The stent of any one of  claims 6 - 12 , wherein the slow release composition comprises at least two, different slow release components. 
     
     
         14 . The stent of any one of  claim 13 , wherein one slow release component releases from 1.0 ng-15 ng IGF-1 within 2 hours after introduction into an individual and a second, different slow release component releases from 1.0 ng-100 ng IGF-1 for up to 72 hours after introduction into an individual. 
     
     
         15 . A slow release composition comprising IGF-1 and at least one biocompatible slow release component. 
     
     
         16 . The slow release composition of  claim 15 , wherein the composition comprises at least one component selected from the group consisting of: 50CP30L40-LL40 (PCL-02), Polyglycolide (PGA), Copolymers of glycolide, Glycolide/L-lactide copolymers (PGA/PLLA), Glycolide/trimethylene carbonate copolymers (PGS/TMC), Polylactides (PLA), Stereo-copolymers of PLA, Poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers, Copolyers of PLA, Lactide/tetramethylglycolide copolymers, Lactide/trimethylene carbonate copolymers, Lactide/α-valerolactone copolymers, Lactide/ε-caprolactone copolymers, Hyaluronic acid and its derivatives, Polydepsipeptides, PLA/polyethylene oxide copolymers, Unsymmetrical 3,6-substitute poly-1,4-dioxane-2,5-di-ones, Poly-βhydroxybutyrate (PHBA), PHBA A/β-hydroxyvalerate copolymers (PHBA/HVA), Poly-p-dioxanone (PDS), Poly-α-valerolactone, Poly-ε-caprolactone, Methylmethacrylate-N-vinyl pyrrolidine copolymers, Polyesteramides, Polyesters of oxalic acid, Polydihydropyranes, Polyalkyl-2-cyanoacrylates, Polyurethanes (PU), Polyvinylalcohol (PVA), Polypeptides, Poly-β-malic acid (PMLA), Poly-β-alcanoic acids and alginates. 
     
     
         17 . The slow release composition of  claim 15  or  16 , wherein IGF-1 is administered in a single intracoronary injection. 
     
     
         18 . The slow release composition of any of  claims 15  to  17 , wherein the composition releases from about 1.0 ng of IGF-1 to about 100 ng of IGF-1 within 24 hours after injection. 
     
     
         19 . The slow release composition of any of  claims 15 - 18 , wherein the IGF-1 content is from about 1.0 ng IGF-1 to about 100 ng IGF-1. 
     
     
         20 . The slow release composition of any of  claims 15 - 19 , wherein the composition releases from about 1.0 ng IGF-1 to about 100 ng IGF-1 into cardiac muscle within 48 hours after intracoronary injection. 
     
     
         21 . The slow release composition of any of  claims 15 - 20 , wherein the composition releases from about 1.0 ng-2.0 ng, from about 1.0 ng-5.0 ng, from about 1.0 ng-10 ng, from about 1.0 ng-20 ng, from about 1.0 ng-30 ng, from about 1.0 ng-40 ng, from about 1.0 ng-60 ng, from about 1.0 ng-80 ng or from about 1.0 ng-100 ng IGF-1 within 48 hours after intracoronary injection. 
     
     
         22 . The slow release composition of any of  claims 15 - 21 , wherein the composition releases from 1.0 ng-15 ng IGF-1 within 2 hours after intracoronary injection. 
     
     
         23 . The slow release composition of any of  claims 15 - 21 , wherein the composition comprises at least two, different slow release components. 
     
     
         24 . The slow release composition of  claim 23 , wherein one slow release component releases from 1.0 ng-15 ng IGF-1 within 2 hours after intracoronary injection and a second, different slow release component releases from 1.0 ng-100 ng IGF-1 for up to 72 hours after intracoronary injection. 
     
     
         25 . A method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising intracoronary injection of a slow release composition comprising (a) a therapeutically effective amount of IGF-1 and (b) a slow release component in an individual (in whom a myocardial infarct has occurred) within 72 hours after occurrence of the myocardial infarct, wherein the therapeutically effective amount is an amount that reduces the extent to which cell death occurs in heart muscle/tissue. 
     
     
         26 . A method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising administering to an individual a single intracoronary injection of a slow-release composition that comprises IGF-1 and a slow release component, within 72 hours after myocardial infarction and in a location that results in delivery of IGF-1 to the area of risk in an amount sufficient to reduce the extent to which cell death occurs in heart muscle/tissue. 
     
     
         27 . The method of  claim 25 , wherein the slow release composition is administered in a single injection. 
     
     
         28 . The method of any one of  claims 25  to  27 , wherein the slow release composition is injected within 5 minutes, within 10 minutes, within 30 minutes, within 1 hour, within 2 hours, within 5 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 48 hours, within 60 hours or within 72 hours after occurrence of myocardial infarct. 
     
     
         29 . The method of any one of  claims 25  to  28 , wherein IGF-1 is administered within 24 to 48 hours after occurrence of myocardial infarct. 
     
     
         30 . The method of any of  claims 25 - 29 , wherein the therapeutically effective amount of IGF-1 is from about 1.0 ng of IGF-1 to about 100 ng of IGF-1. 
     
     
         31 . The method of any of  claims 25 - 30 , wherein the therapeutically effective amount of IGF-1 is from about 1.0 ng-2.0 ng, from about 1.0 ng-5.0 ng, from about 1.0 ng-10 ng, from about 1.0 ng-20 ng, from about 1.0 ng-30 ng, from about 1.0 ng-40 ng, from about 1.0 ng-60 ng, from about 1.0 ng-80 ng or from about 1.0 ng-100 ng. 
     
     
         32 . The method of any one of  claims 25 - 31 , wherein the slow release composition comprises one slow release component. 
     
     
         33 . The method of any of  claims 25 - 32 , wherein the slow release composition comprises at least two different slow release components. 
     
     
         34 . The method of any of  claims 25 - 33 , wherein the slow release composition comprises at least one component selected from the group consisting of: 50CP30L40-LL40, Polyglycolide (PGA), Copolymers of glycolide, Glycolide/L-lactide copolymers (PGA/PLLA), Glycolide/trimethylene carbonate copolymers (PGS/TMC), Polylactides (PLA), Stereo-copolymers of PLA, Poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers, Copolyers of PLA, Lactide/tetramethylglycolide copolymers, Lactide/trimethylene carbonate copolymers, Lactide/α-valerolactone copolymers, Lactide/ε-caprolactone copolymers, Hyaluronic acid and its derivatives, Polydepsipeptides, PLA/polyethylene oxide copolymers, Unsymmetrical 3,6-substitute poly-1,4-dioxane-2,5-di-ones, Poly-βhydroxybutyrate (PHBA), PHBA A/β-hydroxyvalerate copolymers (PHBA/HVA), Poly-p-dioxanone (PDS), Poly-α-valerolactone, Poly-ε-caprolactone, Methylmethacrylate-N-vinyl pyrrolidine copolymers, Polyesteramides, Polyesters of oxalic acid, Polydihydropyranes, Polyalkyl-2-cyanoacrylates, Polyurethanes (PU), Polyvinylalcohol (PVA), Polypeptides, Poly-β-malic acid (PMLA), Poly-β-alcanoic acids and alginates. 
     
     
         35 . The method of any of  claims 25 - 34 , wherein the therapeutically effective amount of IGF-1 is released within 48 hours after injection. 
     
     
         36 . The method of  claim 33 , wherein one slow release component releases a therapeutically effective amount of IGF-1 within 2 hours after injection and a second, different slow release component releases a therapeutically effective amount of IGF-1 for up to 72 hours after injection. 
     
     
         37 . A method of delivering IGF-1 to the site of a myocardial infarct comprising injecting via intracoronary artery a slow release composition comprising (a) a therapeutically effective amount of IGF-1 and (b) a slow release composition in an individual in whom a myocardial infarct has occurred, within 72 hours after occurrence of the myocardial infarct. 
     
     
         38 . The method of  claim 37 , wherein the slow release composition is injected as a single injection within 2 hours after myocardial infarct occurs. 
     
     
         39 . The method of  claim 38 , wherein the slow release composition is injected as a single dose within 5 minutes, within 10 minutes, within 30 minutes, within 1 hour, within 2 hours, within 5 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 48 hours, within 60 hours or within 72 hours after occurrence of myocardial infarct. 
     
     
         40 . The method of any of  claims 37 - 39 , wherein IGF-1 is administered by a single injection via coronary artery. 
     
     
         41 . The method of any of  claims 37 - 40 , wherein the therapeutically effective amount of IGF-1 is from about 1.0 ng of IGF-1 to about 100 ng of IGF-1. 
     
     
         42 . The method of any of  claims 37 - 41 , wherein the therapeutically effective amount of IGF-1 is from about 1.0 ng-2.0 ng, from about 1.0 ng-5.0 ng, from about 1.0 ng-10 ng, from about 1.0 ng-20 ng, from about 1.0 ng-30 ng, from about 1.0 ng-40 ng, from about 1.0 ng-60 ng, from about 1.0 ng-80 ng or from about 1.0 ng-100 ng. 
     
     
         43 . The method of any one of  claims 37 - 42 , wherein the slow release composition comprises at least one component selected from the group consisting of: 50CP30L40-LL40, Polyglycolide (PGA), Copolymers of glycolide, Glycolide/L-lactide copolymers (PGA/PLLA), Glycolide/trimethylene carbonate copolymers (PGS/TMC), Polylactides (PLA), Stereo-copolymers of PLA, Poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers, Copolyers of PLA, Lactide/tetramethylglycolide copolymers, Lactide/trimethylene carbonate copolymers, Lactide/α-valerolactone copolymers, Lactide/ε-caprolactone copolymers, Hyaluronic acid and its derivatives, Polydepsipeptides, PLA/polyethylene oxide copolymers, Unsymmetrical 3,6-substitute poly-1,4-dioxane-2,5-di-ones, Poly-βhydroxybutyrate (PHBA), PHBA A/β-hydroxyvalerate copolymers (PHBA/HVA), Poly-p-dioxanone (PDS), Poly-α-valerolactone, Poly-ε-caprolactone, Methylmethacrylate-N-vinyl pyrrolidine copolymers, Polyesteramides, Polyesters of oxalic acid, Polydihydropyranes, Polyalkyl-2-cyanoacrylates, Polyurethanes (PU), Polyvinylalcohol (PVA), Polypeptides, Poly-β-malic acid (PMLA), Poly-β-alcanoic acids and alginates. 
     
     
         44 . The method of any of  claims 37 - 42 , wherein the slow release composition comprises at least two different slow release components. 
     
     
         45 . The method of  claim 44 , wherein the slow release composition comprises at least two components selected from the group consisting of 50CP30L40-LL40, Polyglycolide (PGA), Copolymers of glycolide, Glycolide/L-lactide copolymers (PGA/PLLA), Glycolide/trimethylene carbonate copolymers (PGS/TMC), Polylactides (PLA), Stereo-copolymers of PLA, Poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers, Copolyers of PLA, Lactide/tetramethylglycolide copolymers, Lactide/trimethylene carbonate copolymers, Lactide/α-valerolactone copolymers, Lactide/ε-caprolactone copolymers, Hyaluronic acid and its derivatives, Polydepsipeptides, PLA/polyethylene oxide copolymers, Unsymmetrical 3,6-substitute poly-1,4-dioxane-2,5-di-ones, Poly-βhydroxybutyrate (PHBA), PHBA A/β-hydroxyvalerate copolymers (PHBA/HVA), Poly-p-dioxanone (PDS), Poly-α-valerolactone, Poly-ε-caprolactone, Methylmethacrylate-N-vinyl pyrrolidine copolymers, Polyesteramides, Polyesters of oxalic acid, Polydihydropyranes, Polyalkyl-2-cyanoacrylates, Polyurethanes (PU), Polyvinylalcohol (PVA), Polypeptides, Poly-β-malic acid (PMLA), Poly-β-alcanoic acids and alginates. 
     
     
         46 . The method of any of  claims 37 - 45 , wherein the therapeutic amount of IGF-1 is released within 48 hours after injection via intracoronary artery. 
     
     
         47 . The method of  claim 44 , wherein one slow release component releases a therapeutically effective amount of IGF-1 within 2 hours after injection and a second, different slow release component releases a therapeutically effective amount of IGF-1 for up to 72 hours. 
     
     
         48 . A method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising controlled release of IGF-1 into heart muscle/tissue, wherein a chemically modified IGF-1 RNA is administered to an individual for transient IGF-1 expression, which results in reduced cell death in heart muscle/tissue in the individual. 
     
     
         49 . A method of reducing cell death in heart muscle/tissue in an individual resulting from myocardial infarction, comprising administering to the individual chemically modified IGF-1 RNA that is transiently expressed in the individual into heart muscle/tissue in an amount sufficient to provide a cytoprotective effect. 
     
     
         50 . A slow release composition comprising (a) a therapeutically effective amount of IGF-1 and (b) a slow release component, for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising intracoronary injection of said slow release composition in an individual (in whom a myocardial infarct has occurred) within 72 hours after occurrence of the myocardial infarct, wherein the therapeutically effective amount is an amount that reduces the extent to which cell death occurs in heart muscle/tissue. 
     
     
         51 . A slow-release composition that comprises IGF-1 and a slow release component for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising administering to an individual a single intracoronary injection of said slow-release composition within 72 hours after myocardial infarction and in a location that results in delivery of IGF-1 to the area of risk in an amount sufficient to reduce the extent to which cell death occurs in heart muscle/tissue. 
     
     
         52 . The composition for use according to  claim 50  or  51  wherein the method is as defined in any one of  claims 27 - 36 . 
     
     
         53 . A slow release composition comprising (a) a therapeutically effective amount of IGF-1 and (b) a slow release composition, for use in a method of delivering IGF-1 to the site of a myocardial infarct comprising injecting via intracoronary artery said slow release composition in an individual in whom a myocardial infarct has occurred, within 72 hours after occurrence of the myocardial infarct. 
     
     
         54 . The composition for use according to  claim 53  wherein the method is as defined in any one of  claims 38 - 47 . 
     
     
         55 . Chemically modified IGF-1 RNA for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, comprising controlled release of IGF-1 into heart muscle/tissue, wherein said chemically modified IGF-1 RNA is administered to an individual for transient IGF-1 expression, which results in reduced cell death in heart muscle/tissue in the individual. 
     
     
         56 . Chemically modified IGF-1 RNA for use in a method of reducing cell death in heart muscle/tissue in an individual resulting from myocardial infarction, comprising administering to the individual said chemically modified IGF-1 RNA that is transiently expressed in the individual into heart muscle/tissue in an amount sufficient to provide a cytoprotective effect. 
     
     
         57 . The stent of any one of  claims 1 - 14  for use in therapy or prophylaxis. 
     
     
         58 . The stent of any one of  claims 1 - 14  for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction. 
     
     
         59 . The composition of any one of  claims 15 - 24  for use in therapy or prophylaxis. 
     
     
         60 . The composition of any one of  claims 15 - 24  for use in a method as defined in any one of  claims 25 - 47 . 
     
     
         61 . Use of IGF-1 in the manufacture of a stent as defined in any one of  claims 1 - 14  for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction. 
     
     
         62 . Use of a slow release composition as defined in any one of  claims 15 - 24  for the manufacture of a medicament for use in a method of reducing cell death in heart muscle/tissue resulting from myocardial infarction, for example in a method as defined in any one of  claims 25 - 47 . 
     
     
         63 . Use of chemically modified IGF-1 RNA for the manufacture of a medicament for use in a method as defined in  claim 55  or  56 .